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Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival

Abstract

Prophylactic donor lymphocyte infusion (pDLI) is a potential intervention to prolong remission for patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT), however, the optimal timing and dose are unknown. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) at day 60 followed by dose escalation of pDLI after alemtuzumab-based, T-cell depleted conditioning for patients with high-risk hematologic malignancies. pDLI were administered at day 75 to day 90 and again in 4–8 week intervals with receipt of up to 5 pDLI infusions. Fourty-six patients with matched-related donors (MRD) and 29 patients with matched-unrelated donors (MUD) were considered. Twenty-eight MRD patients were able to undergo WOI, 26 patients (93%) received at least 1 DLI, 16 patients (57%) received 3+, and 7 patients (25%) received 5 pDLI. Only 7 MUD patients were able to undergo WOI, 4 (57%) received at least 1 pDLI, 1 patient (14%) received 3 DLI, and no patients received all 5. Median PFS for patients on the study was 366 days. The estimated 2-year PFS and OS rates for all patients were 41% (95% CI, 32–54%) and 51% (95% CI, 41–63%) compared with 57% (95% CI, 41–77%) and 67% (95% CI, 52–86%) for patients who received at least one pDLI. In addition, MRD patients receiving pDLI had faster immune re-constitution and improved donor chimerism. Our trial proposes a novel dosage and treatment schedule for pDLI that is tolerable for patients who have received MRD allo-SCT and leads to improved outcomes.

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Acknowledgements

HL was supported by UCCCC pilot grant, Cancer Research Foundation Young investigator award and K12 Paul Calabresi award. The work is also supported by University of Chicago Cancer Center Support Grant (CA014599).

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HL and AA designed the trial. HL, AA WS, RAL, OO, JK, JL, SK, PR, and MB conducted the clinical trial, collected and analyzed the clinic data. NF collected and prepared patient samples and performed WT1 qRT-PCR. JP and YN contributed to TCR sequencing. SL conducted the statistical analysis of the clinical results. All authors contributed to the data analysis and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hongtao Liu.

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While several co-authors had research support from pharmaceutical companies, or served as consultant or advisory board members for pharmaceutical companies, none has a conflict of interest associated with this current study.

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Kothari, S., Artz, A.S., Lee, S.M. et al. Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival. Bone Marrow Transplant 55, 1161–1168 (2020). https://doi.org/10.1038/s41409-020-0798-4

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